Summary

Idarucizumab is the first agent to be licensed in the UK that reverses the anticoagulant effect of a non‑vitamin K antagonist oral anticoagulant (NOAC). Its action is specific against the NOAC dabigatran etexilate. In the interim analysis of an ongoing, phase III, uncontrolled, cohort study (RE‑VERSE AD; n=90), treatment with a 5 g dose of idarucizumab completely reversed the anticoagulant effect of dabigatran etexilate in adults who had either serious bleeding or required urgent surgery. People may still need other supportive measures, for example blood products, to manage their bleeding and these should be considered as medically appropriate.

Regulatory status: Idarucizumab (Praxbind, Boehringer Ingelheim Limited) was launched in the UK in December 2015. It is licensed for use in adults treated with dabigatran etexilate (Pradaxa, Boehringer Ingelheim Limited) when rapid reversal of its anticoagulant effects is required for emergency surgery or urgent procedures, or in life‑threatening or uncontrolled bleeding.

Effectiveness

In an ongoing, uncontrolled, phase III, cohort study (RE‑VERSE AD) in adults taking dabigatran etexilate who have either serious bleeding or require urgent surgery, interim results from 90 people found treatment with a 5 g dose of idarucizumab:

normalised dilute thrombin time and ecarin clotting time in 88–98% of people (efficacy analysis; n=68 to 81).

Median investigator‑reported time to cessation of bleeding was 11.4 hours (n=35; see the evidence review section for more information).

Normal intraoperative haemostasis was seen in 92% of people (n=36).

Safety

Idarucizumab binds specifically to dabigatran and its metabolites and will not reverse the effects of any other anticoagulant.

Reversing the anticoagulant effect of dabigatran etexilate with idarucizumab exposes people to the thrombotic risk of their underlying disease; restarting anticoagulant therapy should be considered as soon as is medically appropriate (idarucizumab summary of product characteristics).

The summary of product characteristics for idarucizumab states that during the ongoing RE‑VERSE AD study, 26 out of a total of 123 people died. Each of these deaths could be attributed either as a complication of the index event or associated with comorbidities.

The amount of sorbitol contained in each dose of idarucizumab is very high and the summary of product characteristics includes a warning about use in people with hereditary fructose intolerance.

In certain clinical situations, administration of a second 5 g dose of idarucizumab may be considered.

People treated with idarucizumab may still need other supportive measures; these should be considered as medically appropriate.

Introduction and current guidance

Anticoagulant therapy is used for preventing and treating thromboembolism across various clinical indications. Licensed oral anticoagulants that are used in the UK include warfarin, and the NOACs apixaban, dabigatran etexilate, edoxaban and rivaroxaban.

The most common adverse effect of anticoagulants is bleeding, ranging from mild events to serious and fatal haemorrhage. Until recently, there were no specific antidotes for NOACs, unlike warfarin. Idarucizumab is the first agent to be licensed to reverse the anticoagulant effect of a NOAC, and it is specific for dabigatran etexilate.

This evidence summary looks at the evidence for the efficacy and safety of idarucizumab for reversing the anticoagulant effect of dabigatran etexilate.

Product overview

Idarucizumab (Praxbind, Boehringer Ingelheim Limited) is a humanised monoclonal antibody fragment (Fab) with a very high affinity to dabigatran. It potently and specifically binds to dabigatran and its metabolites, thereby preventing dabigatran from exerting its anticoagulant effect. Its action is specific to dabigatran etexilate and so it will not reverse the action of other anticoagulants (idarucizumab summary of product characteristics).

Idarucizumab is licensed for use in adults treated with dabigatran etexilate (Pradaxa, Boehringer Ingelheim Limited) when rapid reversal of its anticoagulant effects is required:

for emergency surgery or urgent procedures

in life‑threatening or uncontrolled bleeding.

The recommended dose of idarucizumab is 5 g given intravenously as 2 consecutive infusions of 2.5 g/50 ml over 5 to 10 minutes each or as 2 consecutive 2.5 g bolus injections. Administration of a second 5 g dose of idarucizumab may be considered in the following clinical situations:

recurrence of clinically relevant bleeding together with prolonged clotting times or

if potential re‑bleeding would be life‑threatening and prolonged clotting times are observed or

patients require a second emergency surgery or urgent procedure and have prolonged clotting times.

Evidence review

This evidence summary includes the interim analysis of an ongoing, phase III, prospective, cohort study (NCT02104947; RE‑VERSE AD) reported by Pollack et al. 2015. This included 90 adults aged 18 years and above who were taking dabigatran etexilate and had either overt, uncontrollable, or life‑threatening bleeding (group A, n=51) or required surgery or other invasive procedures that could not be delayed for at least 8 hours and for which normal haemostasis was required (group B, n=39).

The primary end point of the study is the maximum percentage reversal of the anticoagulant effect of dabigatran etexilate at any point from the end of the first infusion of idarucizumab to 4 hours after the second infusion, based on measurement of the dilute thrombin time or ecarin clotting time. In the interim analysis, 90 people were enrolled and given idarucizumab because they met inclusion criteria for the study. However, 22 people were subsequently found to have normal dilute thrombin times at baseline, and 9 people were found to have normal ecarin clotting times, so they were excluded from the efficacy analysis.

In 68 people with elevated dilute thrombin time, and 81 people with elevated ecarin clotting time at baseline, the median maximum reversal of the anticoagulant effect of dabigatran etexilate was 100% (95% confidence interval [CI] 100 to 100%). The dilute thrombin time returned to normal in 93–98% of people and the ecarin clotting time returned to normal in 88–89% of people after a 5 g dose of idarucizumab.

The mortality rate in the interim analysis of the RE‑VERSE AD study was 20% with 18/90 people dying. Half of the deaths occurred within 96 hours of treatment with idarucizumab and appeared to be related to the index event. The remaining deaths occurred after 96 hours and appeared to be related to existing comorbidities rather than the index event. Participants in the RE‑VERSE AD study include high risk populations such as those with intracranial bleeding in whom the mortality rate is expected to be high.

Other clinical outcomes reported in the interim analysis of the study were median investigator‑reported time to cessation of bleeding in group A (which was 11.4 hours) and intraoperative haemostasis in group B (which was reported to be normal in 92% of people). Cessation of bleeding was subjective and was difficult to assess in some people (such as those with intracranial bleeding) because investigators could not easily visualise or identify the bleeding site.

In the interim analysis of RE‑VERSE AD, 5/90 people had a thrombotic event during the study follow‑up. Only 1 of these people had a thrombotic event within 72 hours of receiving idarucizumab; and none of these people were receiving antithrombotic treatment when the event occurred. The summary of product characteristics for idarucizumab states that people being treated with dabigatran etexilate have underlying disease states that put them at higher risk of thromboembolic events. Reversing the anticoagulant effect of dabigatran etexilate exposes people to the thrombotic risk of their underlying disease. Therefore restarting anticoagulant therapy should be considered as soon as is medically appropriate to reduce this risk. Dabigatran etexilate can be restarted after 24 hours if the person is clinically stable and adequate haemostasis has been achieved. Other antithrombotic therapy, for example low‑molecular weight heparin, can be started at any time after administration of idarucizumab, if the patient is clinically stable and adequate haemostasis has been achieved.

According to the summary of product characteristics for idarucizumab, no adverse reactions to idarucizumab were identified when safety was evaluated in 224 healthy people as well as 123 people in the ongoing RE‑VERSE AD study. In the interim analysis of RE‑VERSE AD, Pollack et al. 2015 reported that 21 people experienced a serious adverse event. These included the 5 thrombotic events and 18 deaths discussed above as well as gastrointestinal haemorrhage (n=2), postoperative wound infection (n=1), delirium (n=1), right ventricular failure (n=1) and pulmonary oedema (n=1). Some people had more than 1 event. The summary of product characteristics for idarucizumab states that each of the deaths that occurred could be attributed either as a complication of the index event or associated with comorbidities, and each of the thrombotic events that occurred could be attributed to the person's underlying medical condition.

The strengths of the of the RE‑VERSE AD study include its broad inclusion criteria, such as people with acute trauma and those who were expected to die within 3 days, or to require surgery within 24 hours. It also included older people (mean age 76.7 years) and a high proportion of people with intracranial bleeding (20%). However the interim analysis was based on a limited data set of only 90 people, of which only 68 to 81 people were included in the efficacy analyses. The European Medicines Agency agreed that the use of a comparator arm would have been unethical and that all standard supportive care treatments should be allowed (European public assessment report for idarucizumab). However, the uncontrolled design of the study has inherent limitations, making it difficult to assess the clinical benefit of idarucizumab in people with (or at risk of) bleeding associated with dabigatran etexilate. The primary outcome of the RE‑VERSE AD study, reversal of the anticoagulant effect, was suitable to demonstrate the ability of idarucizumab to reverse the effect of dabigatran etexilate. This reversal of elevated anticoagulation effect was a surrogate for clinical efficacy, and the clinical benefit of this outcome depends on the individual patient clinical situation, disease or bleeding severity or location of the bleeding (European public assessment report for idarucizumab).

Context

There are currently no other licensed agents to reverse the anticoagulant effect of dabigatran etexilate (or any other NOAC).

The dabigatran etexilate summary of product characteristics states that in the event of haemorrhagic complications, treatment must be stopped and general supportive measures such as surgical haemostasis and blood volume replacement carried out. In people undergoing surgery or invasive procedures, temporarily stopping dabigatran etexilate may be required. The decision to stop dabigatran etexilate and when to stop it will depend on the person's risk of having a thromboembolic event, their renal function and the bleeding risk associated with the procedure (see the dabigatran etexilate summary of product characteristics for more information).

The dabigatran etexilate summary of product characteristics now also states that when rapid reversal of the anticoagulant effects of dabigatran is required (for emergency surgery, urgent procedures, or life‑threatening or uncontrolled bleeding) the specific reversal agent idarucizumab is available. Idarucizumab can be used in conjunction with standard supportive measures, which should be considered as medically appropriate.

Estimated impact for the NHS

Idarucizumab is licensed for use in adults when rapid reversal of dabigatran etexilate's anticoagulant effects is required for emergency surgery or urgent procedures, or in life‑threatening or uncontrolled bleeding. Idarucizumab is likely to be an important treatment option for people with life‑threatening bleeding and those who need urgent surgery associated with a bleeding risk. The decision on whether to treat people with idarucizumab will need to be made on an individual patient basis, taking into account factors such as the location, size and severity of the bleeding (or the risk of bleeding associated with the surgical intervention or invasive procedure), the thrombotic risk of their underlying disease, and any comorbidities the person has. Standard supportive measures should be considered as medically appropriate.

Dabigatran etexilate has a half‑life of approximately 12–14 hours in people with normal renal function, but this is increased in people with renal impairment. Therefore the timing of the last dose of dabigatran etexilate is likely to be a factor in whether reversal of its anticoagulant effect is needed.

People who are treated with idarucizumab may still need other supportive measures, for example blood products, to manage their bleeding. These should be considered as medically appropriate. In certain clinical situations, administration of a second 5 g dose of idarucizumab may be considered (see the idarucizumab summary of product characteristics for details). This would be, at an additional cost of £2,400 excluding VAT per 5 g dose (MIMS, April 2016).

'Evidence summaries: new medicines' provide summaries of key evidence for selected new medicines, or for existing medicines with new indications or formulations, that are considered to be of significance to the NHS. The strengths and weaknesses of the relevant evidence are critically reviewed within this summary to provide useful information for those working on the managed entry of new medicines for the NHS, but this summary is not NICE guidance.